- Integrin αvβ6 (IC50 = 29.8 nM) [3]
- Integrin αvβ1 (IC50 = 19.2 nM) [3]

Inhibiting TGF - β activation: Bexotegrast (PLN - 74809) can inhibit the activation of TGF - β induced by integrins αvβ6 and αvβ1 in vitro. Through ligand - binding, cell adhesion, and TGF - β cell activation assays, it is found that the drug can reduce the expression of type I collagen gene by blocking the integrin - mediated TGF - β activation pathway, which is verified in precision - cut lung slices from idiopathic pulmonary fibrosis patients [3]

Anti - fibrotic effect: In bleomycin - challenged mice, Bexotegrast (PLN - 74809) can dose - dependently inhibit pulmonary Smad3 phosphorylation and collagen deposition, reducing the burden of pulmonary fibrosis. It shows a better anti - fibrotic effect than nintedanib or pirfenidone, and can more effectively reduce the collagen gene expression in the lung tissue of fibrotic mice [3]

Bleomycin - induced lung fibrosis mouse model: Induce lung fibrosis in mice with bleomycin. Divide the mice into different groups, and administer Bexotegrast (PLN - 74809) to the experimental groups at different doses, while the control group is given a placebo. After a certain period of treatment, sacrifice the mice, collect lung tissues, and detect the changes of pulmonary collagen deposition and Smad3 phosphorylation to evaluate the anti - fibrotic effect of the drug [3]

Pharmacokinetics [2]
Predicted total and unbound exposures (maximum concentration and area under the concentration time curve from Time 0 to 24 hours postdose) of bexotegrast in participants with IPF increased approximately proportionally with dose (see Tables E3 and E4).

Safety and Tolerability through Week 12 [2]
Overall, bexotegrast demonstrated a favorable safety and tolerability profile over 12 weeks of treatment (Tables 2, 3, E1, and E2 in the online supplement). The majority of TEAEs were mild or moderate in severity. The most common TEAEs are presented in Table 2. Diarrhea was the most common TEAE, occurring in 15 participants (16.9%) in the bexotegrast (pooled) group and 3 participants (9.7%) in the placebo group. Of the participants reporting diarrhea, 13/15 (86.7%) participants in the bexotegrast group and 1/3 (33.3%) participants in the placebo group were receiving nintedanib background therapy; one participant (6.7%) with diarrhea in the bexotegrast group was receiving pirfenidone (Table 3). The remaining participant with diarrhea who received bexotegrast monotherapy had preexisting ulcerative colitis. Most events of diarrhea (14/15; 93.3%) were mild to moderate in severity; one participant receiving bexotegrast and pirfenidone had Grade 3 diarrhea. Four participants interrupted bexotegrast treatment because of intercurrent coronavirus disease (COVID-19) (n = 1), diarrhea (n = 2), and ileus and acute kidney injury (n = 1). Two participants discontinued bexotegrast because of mild diarrhea (n = 1 receiving background nintedanib; n = 1 receiving no background therapy and having preexisting ulcerative colitis). Dose reduction of bexotegrast was not allowed per protocol. No serious adverse events were assessed as being related to the study drug.
TEAEs of IPF/pulmonary fibrosis were reported in 2.3% of participants in the bexotegrast group and 9.7% of participants in the placebo group. Only one of these events was reported as an acute exacerbation of IPF in a participant who had completed 12 weeks of treatment with 160 mg bexotegrast and experienced the event 11 days after the last dose. The event was not considered to be drug related and resolved the following day after treatment in hospital with corticosteroids and antibiotics. One participant with gender-age-physiology Stage III IPF and preexisting coronary artery disease and chronic refractory atrial fibrillation in the 320-mg bexotegrast group experienced a serious and fatal adverse event of acute respiratory failure after elective atrioventricular node ablation. There were no notable changes in laboratory parameters, vital signs, physical examination findings, or electrocardiography findings associated with the study drug. Overall, bexotegrast was well tolerated when used in combination with IPF background therapy or when used as monotherapy (Tables 3, E1, and E2).

[1]. De novo design of highly selective miniprotein inhibitors of integrins αvβ6 and αvβ8. Nat Commun. 2023 Sep 13;14(1):5660.

[2]. Bexotegrast in Patients with Idiopathic Pulmonary Fibrosis: The INTEGRIS-IPF Clinical Trial. Am J Respir Crit Care Med. 2024 Aug 15;210(4):424-434.

[3]. Dual inhibition of αvβ6 and αvβ1 reduces fibrogenesis in lung tissue explants from patients with IPF. Respir Res. 2021 Oct 19;22(1):265.

αv integrins are key regulators of TGF - β activation and fibrogenesis in pulmonary fibrosis models. αvβ6 and αvβ1 are highly expressed in the lung tissue of patients with idiopathic pulmonary fibrosis, but rarely expressed in normal tissues. Bexotegrast (PLN - 74809) is a small - molecule oral drug, which blocks the activation of TGF - β by inhibiting αvβ6 and αvβ1, and may slow down or even stop the fibrosis process in patients with idiopathic pulmonary fibrosis. It is in phase Ⅱ/Ⅲ clinical trials for the treatment of IPF [3]

C27H38CL2N6O3

565.54

2775365-40-5

2376257-44-0

Typically exists as solids at room temperature

PLN-74809 hydrochloride; PLN-74809 HCl; PLN74809 hydrochloride; orb1739963; 2775365-40-5

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)

May dissolve in DMSO (in most cases), if not, try other solvents such as H2O, Ethanol, or DMF with a minute amount of products to avoid loss of samples

Note: Listed below are some common formulations that may be used to formulate products with low water solubility (e.g. < 1 mg/mL), you may test these formulations using a minute amount of products to avoid loss of samples.

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Injection Formulation 1: DMSO : Tween 80： Saline = 10 : 5 : 85 (i.e. 100 μL DMSO stock solution → 50 μL Tween 80 → 850 μL Saline)
*Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH ₂ O to obtain a clear solution.
Injection Formulation 2: DMSO : PEG300 ：Tween 80 : Saline = 10 : 40 : 5 : 45 (i.e. 100 μL DMSO → 400 μLPEG300 → 50 μL Tween 80 → 450 μL Saline)
Injection Formulation 3: DMSO : Corn oil = 10 : 90 (i.e. 100 μL DMSO → 900 μL Corn oil)
Example: Take the Injection Formulation 3 (DMSO : Corn oil = 10 : 90) as an example, if 1 mL of 2.5 mg/mL working solution is to be prepared, you can take 100 μL 25 mg/mL DMSO stock solution and add to 900 μL corn oil, mix well to obtain a clear or suspension solution (2.5 mg/mL, ready for use in animals).

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Injection Formulation 4: DMSO : 20% SBE-β-CD in saline = 10 : 90 [i.e. 100 μL DMSO → 900 μL (20% SBE-β-CD in saline)]
*Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution.
Injection Formulation 5: 2-Hydroxypropyl-β-cyclodextrin : Saline = 50 : 50 (i.e. 500 μL 2-Hydroxypropyl-β-cyclodextrin → 500 μL Saline)
Injection Formulation 6: DMSO : PEG300 : castor oil : Saline = 5 : 10 : 20 : 65 (i.e. 50 μL DMSO → 100 μLPEG300 → 200 μL castor oil → 650 μL Saline)
Injection Formulation 7: Ethanol : Cremophor : Saline = 10： 10 : 80 (i.e. 100 μL Ethanol → 100 μL Cremophor → 800 μL Saline)
Injection Formulation 8: Dissolve in Cremophor/Ethanol (50 : 50), then diluted by Saline
Injection Formulation 9: EtOH : Corn oil = 10 : 90 (i.e. 100 μL EtOH → 900 μL Corn oil)
Injection Formulation 10: EtOH : PEG300：Tween 80 : Saline = 10 : 40 : 5 : 45 (i.e. 100 μL EtOH → 400 μLPEG300 → 50 μL Tween 80 → 450 μL Saline)

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Oral Formulation 1: Suspend in 0.5% CMC Na (carboxymethylcellulose sodium)
Oral Formulation 2: Suspend in 0.5% Carboxymethyl cellulose
Example: Take the Oral Formulation 1 (Suspend in 0.5% CMC Na) as an example, if 100 mL of 2.5 mg/mL working solution is to be prepared, you can first prepare 0.5% CMC Na solution by measuring 0.5 g CMC Na and dissolve it in 100 mL ddH2O to obtain a clear solution; then add 250 mg of the product to 100 mL 0.5% CMC Na solution, to make the suspension solution (2.5 mg/mL, ready for use in animals).

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Oral Formulation 3: Dissolved in PEG400
Oral Formulation 4: Suspend in 0.2% Carboxymethyl cellulose
Oral Formulation 5: Dissolve in 0.25% Tween 80 and 0.5% Carboxymethyl cellulose
Oral Formulation 6: Mixing with food powders

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Note: Please be aware that the above formulations are for reference only. InvivoChem strongly recommends customers to read literature methods/protocols carefully before determining which formulation you should use for in vivo studies, as different compounds have different solubility properties and have to be formulated differently.

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 (Please use freshly prepared in vivo formulations for optimal results.)